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LUPRON: Never Approved For Infertility Treatment
DAILY Lupron Injections are NOT approved for infertility treatment.
DAILY Lupron Injections are ONLY approved for men with advanced prostate cancer.
I. Dose Used For Infertility Treatment Is High
Lupron is available in the United States in two forms:
1. Daily Lupron Injection = active ingredient is Leuprolide Acetate
2. Monthly Lupron Depot = active ingredient is Leuprolide Acetate
1. Daily Lupron Injection:
0 . 5 mg of Leuprolide Acetate per injection = . 1 ml of Lupron syringe (liquid) = . 1 cc or 10 units
 1 . 0 mg of Leuprolide Acetate per injection =. 2 ml of Lupron syringe (liquid) = . 2 cc or 20 units
2. Monthly Lupron Depot;
The 3.75mg Monthly Lupron Depot releases 3.75 mg of Leuprolide Acetate PER MONTH.
Table 1. DAILY vs. MONTHLY DOSE of LUPRON (Leuprolide Acetate) RECEIVED

	DAILY Lupron; . 1 ml or . 1 cc or
	DAILY Lupron: . 2 ml or . 2 cc or
	MONTHLY DEPOT

	10 units of Lupron =
	20 units of Lupron =

	. 5 me Leuprolide Acetate
	1. 0 me Leuprolide Acetate
	3.75 mg Leuprolide Acetate
	
1 day:
	.5mg
	1.0 mg
	——
	
7 days (1 week):
	3.5mg
	7.0 mg
	——
	
14 days (2 weeks):
	7.0 mg
	14.0 mg
	____
	
21 days (3 weeks):
	10.5 mg
	21.0 mg
	——
	
28 days (1 month):
	14.0 mg
	28.0 mg
	3.75 mg
	
84 days (3 months):
	42.0 mg
	84.0 mg
	11.25mg
	
168 days (6 months):
	84.0 mg_
	168.0 mg
	22.50mg
	
A) DAILY LUPRON INJECTIONS
1.   Daily Lupron injections were approved by the US Food and Drug Administration (PDA) in 1985 and are only approved for men for "the palliative treatment of ADVANCED PROSTATIC CANCER" as "an alternative form of treatment of prostatic cancer when orchiectomy or estrogen administration are either not indicated or  unacceptable to the patient."(l)
2.
Daily Lupron injections were NOT approved or recommended by the FDA for the treatment of early, less
advanced stages of prostate cancer.
DAILY LUPRON INJECTIONS are NOT APPROVED FOR ANY OTHER CONDITIONS DAILY LUPRON INJECTIONS are NOT APPROVED FOR INFERTILITY TREATMENT
3.   The only FDA studies available for DAILY Lupron Injections were done on men who were terminally ill with prostate cancer and had 2-3 years left to live.
4.   The following studies for DAILY Lupron Injections were NEVER DONE or are NOT BEING MADE AVAILABLE from the FDA:
a.    Long term safety studies are NOT AVAILABLE on men or women who took DAILY Lupron
Injections.
b.   NO INFORMATION IS AVAILABLE on men with LOW STAGE prostate cancer who took DAILY Lupron Injections.
Lupron Daily Injections
PROSTATE CANCER:
	LOW STAGE:
	HIGH STAGE: ADVANCED PROSTATE CANCER

	STAGE A / STAGE B
	STAGE C
	STAGE Dl, D2

	Confined to prostate
	Growth extends beyond prostate locally
	Spread to pelvic lymph nodes, BONE or distant organs
	
Lupron Recommended by the FDA
	NO /NO
	YES
	YES
	
Stage was included in studies when Lupron was being approved
	NO /NO
	NO
Stage C responded poorly to Lupron and was dropped
	YES D2;
Stage Dl responded poorly to Lupron and was dropped
	
FETAL RISK:
According to the package insert, DAILY Lupron injections and MONTHLY Lupron Depot are both rated Pregnancy Category X Drugs by the FDA. "The FDA's Pregnancy Categories are based on the degree to which available information has ruled out risk to the fetus, balanced against the drug's potential benefits to the patient. Ratings range from "A," for drugs that have been tested for teratogenicity under controlled conditions without showing evidence of damage to the fetus, to "D" and "X" for drugs that are definitively teratogenic. The "D" rating is generally reserved for drugs with no safer alternatives. The "X" rating means that there is absolutely no reason to risk using the drug in pregnancy." (1)
•     A = CONTROLLED STUDIES SHOW NO RISK. Adequate, well controlled studies in pregnant women have failed to demonstrate risk to the fetus.
•     B = NO EVIDENCE OF RISK IN HUMANS. Either animal findings show risk, but human findings do not; or, if no adequate human studies have been done, animal findings are negative
•     C = RISK CANNOT BE RULED OUT. Human studies are lacking, and animal studies are either positive for fetal risk, or lacking as well. However, potential benefits may justify the potential risk.
•    D = POSTITIVE EVIDENCE OF RISK. Investigational or post-marketing data show risk to the fetus. Never-the-less, potential benefits may outweigh the potential risk.
•     X = LUPRON = CONTRAEVDICATED IN PREGNANCY. Studies in animals or human, or investigational or post-marketing reports have shown fetal risk which clearly outweighs any possible benefit to the patient. (1)
A teratogen is a drug or other agent that causes abnormal development. (2)
According to the package insert:
•     "Lupron is contraindicated (against medical advice) in women who are or may become pregnant while receiving the drug." (3) This statement appears in the package insert for both DAILY Lupron injections and MONTHLY Lupron Depot. (3)
	
"l/600th the human dose causes major fetal abnormalities in rabbits when administered on day 6 of pregnancy." (3)
"The most frequently observed malformations in rabbits were vertebral anomalies and hydrocephalus (J.D.Miller, personal communication, Tap Pharmaceuticals, Inc., 1992)" (4)
The following congenital anomalies have been reported to the US Food and Drug Administration as part of the Spontaneous Reporting System/Division of Epidemiology and Surveillance:
Congenital Anomaly:
ASD
Cardiac Problems [Unspecified]
Coarction of the Aorta
Enlarged Liver
Enlarged Spleen
Growth Retardation
Hyperplastic Aortic
Imperforate Anus
Rectovaginal Fistula
Spinal Fusion
Spinal Muscular Atrophy
Thirteen Ribs
Underdeveloped Brain (5)
II. QUOTES FROM THE LITERATURE: SAFETY & EFFECTIVENESS
1.   Dr. Porcu and colleagues stated that, "a number of potential disadvantages have been pointed out, including lower and slower ovarian response, impaired luteal function, the development of ovarian cysts, increased incidence of the ovarian hyperstirnulation syndrome, embryo toxicity, fetal toxicity, and impaired child development" with GnRH analogs. (18)
2.   In 1988, the following appeared in the medical literature: "Physicians using Leuprolide Acetate as an adjuvant for ovulation induction should consider obtaining detailed, written informed consent from the patient prior to instituting therapy." (6) It should be noted that informed consent from a patient is generally not required by a doctor when prescribing drugs.
3. According to information that THE NATIONAL LUPRON VICTIMS NETWORK has received "clinical studies for Lupron's use in treating infertility have been discontinued."
4.   Dr. Yoshimura and colleagues stated that, "One cannot exclude the possibility that GnRH-a in pharmacological dosages may be cytotoxic against oocytes..." (7)
5.   Drs. DeSutter, Dhont, and Vandekerckhove concluded: If no selection against chromosomally abnormal oocytes takes place at the time of fertilization, more abnormal oocytes are harvested with GnRHa/hMG protocols than with CC/hMG." (Please note that this study did not employ Lupron, but did employ two other GnRH analogues.) (8)
6.   "They were ... playing with their embryos, as well. Scientists like Cohen noticed that Lupron embryos were different. They grew faster, developed more rapidly. They were more fragile when frozen and less likely to survive thawing. Nobody knew why or what it meant for the long term health of the woman or any resulting child." (9)
7.   Drs. Keenan and Cohen stated, "The rate of development of embryos obtained during down-regulated cycles [with Lupron] was significantly higher than that of embryos developing in conventional stimulation cycles." (10)
8.   Drs. Keenan and Cohen stated, "...there was a decreased incidence of implantation of embryos from patients who were exposed to analogs. It is suggested that embryos from down-regulated cycles should be cryopreserved earlier to correct for their accelerated development." (10)
9.   Dr. Yoshimura and colleagues stated, "GnRH-a[nalogue] acts directly in the mature rabbit follicle to trigger meiotic maturation of oocytes while concomitantly increasing the rate of oocyte degeneration. However, oocytes matured in vitro by GnRH-a, unlike hCG-treated oocytes, are not necessarily cytoplasmically mature." (7)
10. Drs. Kendall, Mathias, and VanHook stated, "Leuprolide Acetate [Lupron] (10-4 to 10-5 M) had a stimulatory effect on spontaneous contractions of human myometrium and fallopian tube in vitro." (12)
11. Dr. Stadtmauer and colleagues stated, There is also evidence that cycles using GnRH analogs and hMG are associated with higher E2 levels and higher doses of hMG but that these oocytes are of lower quality than those retrieved from cycles using hMG alone." (13)
12. Dr. Kingsland and colleagues stated, "GnRH-a[analogues] do not protect against ovarian hyperstimulation, and, in fact, it has been suggested that the risk of hyperstimulation may be slightly higher when GnRH-a are used."(17)
13. Drs. Keenan and Cohen stated, "The proportion of thawed embryos leading to normal birth appeared higher in the control group than in the LA-treated [Lupron] group (7 of 55; 13% versus 1 of 49; 2%, respectively)." (10)
14. Dr. Dodson and colleagues stated, "...the adjunctive use of leuprolide for controlled ovarian hyperstimulation and intrauterine insemination does not improve cycle fecundity compared with treatment cycles that do not include adjunctive leuprolide [Lupron] therapy." (11)
15. Drs. Plosker and Brogden stated, "While some studies demonstrate an improvement in intermediate end-points such as an increased number of mature oocytes retrieved and embryos available for transfer, a significant effect has not been demonstrated on the rate of live births per stimulated cycle." (15)
16. Drs. Plosker and Brogden stated, "In women receiving controlled ovarian stimulation with menoptropins for" IVF of GIFT, "pregnancy rates ranged from approximately 15 to 26% of cycles treated with leuprorelin [Lupron] compared with approximately 15 to 22% of cycles not treated with leuprorelin [Lupron], and were not significantly different between treatment groups." (15)
17. Drs. Plosker and Brogden stated, "Data clearly showing an increase in the number of live births associated with adjuvant leuprorelin [Lupron] therapy are lacking."(15)
18. According to US Food and Drug Administration documents, "Lupron Depot has no effect on pregnancy rates and should not be used as a fertility promoting drug." (16)
19. Dr. Kingsland and colleagues concluded that "there is no overall significant medical advantage of using GnRH-a routinely for all patients undergoing IVF. "(17)
20. Twenty-three patients that conceived with Lupron (duration of exposure to Lupron ranged from 11-28 days; 1-2 mg/day) yielded the following pregnancy outcomes: 2 tubal pregnancies, 2 chemical pregnancies, 6 miscarriages, 9 term deliveries, and 4 ongoing pregnancies. Dr. Karande, Rinehart, Pratt, and Gleicher stated, "The incidence of adverse pregnancy outcome [10/19 = 52.6%] is higher than previously reported in the literature. These data therefore suggest that inadvertant administration of Lupron during early pregnancy may not be as safe as has been assumed." (14)
This Is A Work In Progress
REFERENCES;
1.   Physician's Desk Reference, 1994; p. 2687.
2.   Stedman's Medical Dictionary. Williams and Wilkins Company. Baltimore, 1979.
3.   Physicians Desk Reference, 1992, 1993, 1994, 1995.
4.   Briggs, Freeman & Yaffe. Drugs in Pregnancy and Lactation. 4th Edition.
5.   Adverse Reactions Reported to US Food and Drug Administration as Part of the Spontaneous Reporting System/Division of Epidemiology, through December, 1994.
6.   Leuprolide Acetate: Applications in Gynecology. Current Problems in Obstetrics and Gynecol Pert, November/December, 1988:209-229.
7.   Yoshimura Y, Nakarmira Y, Ando M, Shiokawa S, Koyama N, Nanno T. Direct effect of gonadotropin-releasing hormone agonists on the rabbit ovarian follicle. Fertility & Sterility. 1992;57:5:1091-1097.
8.   DeSutter P, Dhont M, Vandekerckhove D. Hormonal Stimulation for in Vitro Fertilization^ Comparison of
Fertilization Rates and Cytogenetic Findings in Unfertilized Oocytes. Journal of Assisted Reproduction and Genetics. 1992;9:3:254-258.
9.   Hotz RL. Designs on Life. Pocket Books, a division of Simon & Schuster Inc. New York, NY 1991.
10. Keenan D, Cohen J. Stimulation cycles suppressed with gonadotropin-releasing hormone analog yield accelerated embryos. Fertility and Sterility. 1991;55:4:792-796.
11. Dodson WC, Walmer DK, Hughes CL, Yancy SE, Haney AF. Adjunctive Leuprolide Therapy Does Not Improve Cycle Fecundity in Controlled Ovarian Hyperstimulation and Intruterine Insemination of Subfertile Women. Obstetrics and Gynecology. 1991;78:2:187.
12. Kendall J, Mathias J, VanHook J. Leuprolide acetate stimulates smooth muscle of the human reproductive tract. Fertility & Sterility. 1991;56:5:993-994. 
13. StadtmauerL, DitkoffEC, Session D, Kelly A. High dosages of gonadotropins are associated with poor pregnancy outcomes after in vitro fertilization-embryo transfer. Fertility and Sterility. 1994;61:6:1058-1064.
14. Karande VC, Rinehart JS, Pratt DE, Gleicher N. Is the Inadvertant Administration of Leuprolide Acetate in Early Human Pregnancy Truly Associated With Normal Outcomes? Fertility and Sterility. Program Supplement. April 17-21: 1996;A27.
15. Plosker GL, Brogden RN. Leuprorelin. Drugs. 1994;48:6:930-967.
16. US Food and Drug Administration. NDA #20-011
17. Kingsland C, Tan S, Bickerton N, Mason B, Campbell S. The routine use of gonadotropin-releasing hormone
agonists for all patients undergoing in vitro fertilization. Is there any medical advantage? A prospective randomized study. Fertility & sterility. 1992; 57: 4: p. 804-808.
18. Porcu E, Dal Prato L, Seracchioli R, Fabbri R, Petracchi S, Flamigni C. GnRH agonists and assisted reproduction outcome. In Treatment With GnRH Analogs: Controversies and Perspectives, M. Filicori, C. Flamigni (Eds.). The Parthenon Publishing Group. New York. 1996; p. 189.
19. Toguchi H. Formulation Study of Leuprorelin Acetate to Improve Clinical Performance. Clinical Therapeutics. 1992; 14, Suppl. A. p. 121-128.
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